INPP5D

Src homology 2 (SH2) domain containing inositol polyphosphate 5-phosphatase 1 (SHIP1) is an enzyme with phosphatase activity. SHIP1 is structured by multiple domain and is encoded by the INPP5D gene in humans.[5][6][7] SHIP1 is expressed predominantly by hematopoetic cells[8] but also, for example, by osteoblasts[9] and endotelial cells.[10] This phosphatase is important for the regulation of cellular activation. Not only catalytic but also adaptor activities of this protein are involved in this process. Its movement from the cytosol to the cytoplasmic membrane, where predominantly performs its function, is mediated by tyrosine phosphorylation of the intracellular chains of cell surface receptors that SHIP1 binds. Insufficient regulation of SHIP1 leads to different pathologies.[11]

INPP5D
Available structures
PDBOrtholog search: PDBe RCSB
Identifiers
AliasesINPP5D, SHIP, SHIP-1, SHIP1, SIP-145, hp51CN, p150Ship, inositol polyphosphate-5-phosphatase D
External IDsOMIM: 601582 MGI: 107357 HomoloGene: 4046 GeneCards: INPP5D
Gene location (Human)
Chr.Chromosome 2 (human)[1]
Band2q37.1Start233,059,967 bp[1]
End233,207,903 bp[1]
Orthologs
SpeciesHumanMouse
Entrez

3635

16331

Ensembl

ENSG00000168918
ENSG00000281614

ENSMUSG00000026288

UniProt

Q92835

Q9ES52

RefSeq (mRNA)

NM_001017915
NM_005541

NM_001110192
NM_001110193
NM_010566

RefSeq (protein)

NP_001017915
NP_005532

NP_001103662
NP_001103663
NP_034696

Location (UCSC)Chr 2: 233.06 – 233.21 MbChr 1: 87.62 – 87.72 Mb
PubMed search[3][4]
Wikidata
View/Edit HumanView/Edit Mouse

Structure and regulation of activity

SHIP1 is a 145 kDa large protein and member of the inositol polyphosphate-5-phosphatase (INPP5) family. Alternate transcriptional splice variants, encoding different isoforms, have been characterized.[7]

At the N-terminus of the protein, SH2 domain is formed. This domain is important for the interaction of SHIP1 with the phosphorylated protein chains that SHIP1 binds. Highly conserved phosphatase domain is in central part of the protein. This catalytic domain is flanked on the N-terminal side by the PH-like domain that binds phosphatidylinositol-3,4,5-triphosphate (PI(3,4,5)P3) and is overlaped on C-terminus with the C2 domain that binds phosphatidylinositol-3,4-bisphosphate (PI(4, 5)P2). The C-tail is not structured, but contains a proline-rich region that forms the motif for binding SH3 domain and also contains sequence containing tyrosine 915 (Y915) and tyrosine 1022 (Y1022) (in human cell) that is typical for interaction with the phosphotyrosine binding domain (PTB domain).

Phosphatase activity of SHIP1 can be allosteric regulated by phosphorylation of the catalytic domain on serine 440 (Ser440), this phosphorylation is mediated by cAMP-dependent protein kinase A (PKA).[12] Second allosteric regulation is mediated by binding PI(3,4)P2 to the C2 domain.[13] Furthermore, binding PDB domain to C-terminus of SHIP1 is regulated by Y915 and Y1022 phosphorylation.[14]

Function

At the plasma membrane, the protein hydrolyzes the 5' phosphate from phosphatidylinositol (3,4,5)-trisphosphate and inositol-1,3,4,5-tetrakisphosphate, thereby influence the binding of many proteins to the cytoplasmic membrane thus affecting multiple signaling pathways. To access the substrate which is located on the cytoplasmic membrane, SHIP1 move from cytosol to the plasma membrane. This movement is mediated by binding its SH2 domain to the phosphorylated intracellular chains of cell surface receptors. Binding SHIP1 to phosphorylated immunoreceptor tyrosine-based inhibition motifs (ITIM) of FcγRIIB inhibits the activation of B cells including Ca2+ influx.[15] SHIP1 can also interact with other inhibitory receptors and contribute to negative signaling.[16][17] Overall, the protein functions as a negative regulator of cell proliferation and survival. Nevertheles, SHIP1 may also bind to partially phosphorylated immunoreceptor tyrosine-based activation motifs (ITAM) of some cell surface receptors, for example T cell receptor (TCR)[18] and CD79a/b.[19] SHIP1 does not bind only to intracellular chains of cell surface receptor. Its SH2 domain may also interact with phosphorylated cytoplasmic proteins, such as SHC1[20] and DOK1.[21]

The regulation of signaling by SHIP1 is not dependent only on its catalytic activity. SHIP1 can also affect cell signaling pathways independently on its catalytic activity by serving as a bridge for other proteins thereby regulate protein-protein interactions.

Interactions

INPP5D has been shown to interact with DOK2,[22] LYN,[23] CD22,[24] Grb2,[25] CRKL,[26] CD31,[27] DOK1[22][28] and SHC1.[5][22][29][30][31]

Medicines

Poor regulation of the SHIP1 function leads to different pathologies. On the one hand, its increased activity is associated with tumorogenesis. On the other hand, its low activity leads to autoinflammatory diseases.[11] This knowledge is used in drug development. In the case of autoinflammatory diseases, there is an attempt to increase SHIP1 catalytic activity by binding the small molecule to the C2 domain. This molekule should to act as allosteric activator. Currently, some molecules are under development and tested as potential anti-inflammatory drug. AQX-1125 (Rosiptor) and AQX-MN100 are both in clinical trials.[32][33][34]

gollark: Ideally we would be able to run randomised controlled trials on different subregions of the planet.
gollark: I used to just vaguely assume that communism good but impractical, but that's obviously stupid, and then I was somewhat libertarian, but I'm not even sure if that produces good results at all because these things are totally untestable.
gollark: Well, I don't know what economic policy is good any more æææ.
gollark: I see.
gollark: Command-economy "communism", magic-utopia "communism", syndicalist "communism", ...?

References
  1. ENSG00000281614 GRCh38: Ensembl release 89: ENSG00000168918, ENSG00000281614 - Ensembl, May 2017
  2. GRCm38: Ensembl release 89: ENSMUSG00000026288 - Ensembl, May 2017
  3. "Human PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.
  4. "Mouse PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.
  5. Damen JE, Liu L, Rosten P, Humphries RK, Jefferson AB, Majerus PW, Krystal G (February 1996). "The 145-kDa protein induced to associate with Shc by multiple cytokines is an inositol tetraphosphate and phosphatidylinositol 3,4,5-triphosphate 5-phosphatase". Proceedings of the National Academy of Sciences of the United States of America. 93 (4): 1689–93. doi:10.1073/pnas.93.4.1689. PMC 40003. PMID 8643691.
  6. Ware MD, Rosten P, Damen JE, Liu L, Humphries RK, Krystal G (October 1996). "Cloning and characterization of human SHIP, the 145-kD inositol 5-phosphatase that associates with SHC after cytokine stimulation". Blood. 88 (8): 2833–40. doi:10.1182/blood.V88.8.2833.bloodjournal8882833. PMID 8874179.
  7. "Entrez Gene: INPP5D inositol polyphosphate-5-phosphatase, 145kDa".
  8. Geier SJ, Algate PA, Carlberg K, Flowers D, Friedman C, Trask B, Rohrschneider LR (March 1997). "The human SHIP gene is differentially expressed in cell lineages of the bone marrow and blood". Blood. 89 (6): 1876–85. doi:10.1182/blood.V89.6.1876. PMID 9058707. Archived from the original on 2019-01-31. Retrieved 2019-01-30.
  9. Hazen AL, Smith MJ, Desponts C, Winter O, Moser K, Kerr WG (March 2009). "SHIP is required for a functional hematopoietic stem cell niche". Blood. 113 (13): 2924–33. doi:10.1182/blood-2008-02-138008. PMC 2662639. PMID 19074735.
  10. Zippo A, De Robertis A, Bardelli M, Galvagni F, Oliviero S (June 2004). "Identification of Flk-1 target genes in vasculogenesis: Pim-1 is required for endothelial and mural cell differentiation in vitro". Blood. 103 (12): 4536–44. doi:10.1182/blood-2003-11-3827. PMID 14982870.
  11. Kerr WG (January 2011). "Inhibitor and activator: dual functions for SHIP in immunity and cancer". Annals of the New York Academy of Sciences. 1217 (1): 1–17. doi:10.1111/j.1749-6632.2010.05869.x. PMC 4515353. PMID 21155837.
  12. Zhang J, Walk SF, Ravichandran KS, Garrison JC (July 2009). "Regulation of the Src homology 2 domain-containing inositol 5'-phosphatase (SHIP1) by the cyclic AMP-dependent protein kinase". The Journal of Biological Chemistry. 284 (30): 20070–8. doi:10.1074/jbc.M109.016865. PMC 2740433. PMID 19494109.
  13. Ong CJ, Ming-Lum A, Nodwell M, Ghanipour A, Yang L, Williams DE, Kim J, Demirjian L, Qasimi P, Ruschmann J, Cao LP, Ma K, Chung SW, Duronio V, Andersen RJ, Krystal G, Mui AL (September 2007). "Small-molecule agonists of SHIP1 inhibit the phosphoinositide 3-kinase pathway in hematopoietic cells". Blood. 110 (6): 1942–9. doi:10.1182/blood-2007-03-079699. PMID 17502453.
  14. Lamkin TD, Walk SF, Liu L, Damen JE, Krystal G, Ravichandran KS (April 1997). "Shc interaction with Src homology 2 domain containing inositol phosphatase (SHIP) in vivo requires the Shc-phosphotyrosine binding domain and two specific phosphotyrosines on SHIP". The Journal of Biological Chemistry. 272 (16): 10396–401. doi:10.1074/jbc.272.16.10396. PMID 9099679.
  15. Isnardi I, Bruhns P, Bismuth G, Fridman WH, Daëron M (April 2006). "The SH2 domain-containing inositol 5-phosphatase SHIP1 is recruited to the intracytoplasmic domain of human FcgammaRIIB and is mandatory for negative regulation of B cell activation" (PDF). Immunology Letters. 104 (1–2): 156–65. doi:10.1016/j.imlet.2005.11.027. PMID 16406061.
  16. Kuroiwa A, Yamashita Y, Inui M, Yuasa T, Ono M, Nagabukuro A, Matsuda Y, Takai T (January 1998). "Association of tyrosine phosphatases SHP-1 and SHP-2, inositol 5-phosphatase SHIP with gp49B1, and chromosomal assignment of the gene". The Journal of Biological Chemistry. 273 (2): 1070–4. doi:10.1074/jbc.273.2.1070. PMID 9422771.
  17. Eissmann P, Beauchamp L, Wooters J, Tilton JC, Long EO, Watzl C (June 2005). "Molecular basis for positive and negative signaling by the natural killer cell receptor 2B4 (CD244)". Blood. 105 (12): 4722–9. doi:10.1182/blood-2004-09-3796. PMID 15713798.
  18. Osborne MA, Zenner G, Lubinus M, Zhang X, Songyang Z, Cantley LC, Majerus P, Burn P, Kochan JP (November 1996). "The inositol 5'-phosphatase SHIP binds to immunoreceptor signaling motifs and responds to high affinity IgE receptor aggregation". The Journal of Biological Chemistry. 271 (46): 29271–8. doi:10.1074/jbc.271.46.29271. PMID 8910587.
  19. Manno B, Oellerich T, Schnyder T, Corso J, Lösing M, Neumann K, Urlaub H, Batista FD, Engelke M, Wienands J (November 2016). "The Dok-3/Grb2 adaptor module promotes inducible association of the lipid phosphatase SHIP with the BCR in a coreceptor-independent manner". European Journal of Immunology. 46 (11): 2520–2530. doi:10.1002/eji.201646431. hdl:11858/00-001M-0000-002C-799C-E. PMID 27550373.
  20. D'Ambrosio D, Hippen KL, Cambier JC (August 1996). "Distinct mechanisms mediate SHC association with the activated and resting B cell antigen receptor". European Journal of Immunology (in French). 26 (8): 1960–5. doi:10.1002/eji.1830260842. PMID 8765045.
  21. Lemay S, Davidson D, Latour S, Veillette A (April 2000). "Dok-3, a novel adapter molecule involved in the negative regulation of immunoreceptor signaling". Molecular and Cellular Biology. 20 (8): 2743–54. doi:10.1128/mcb.20.8.2743-2754.2000. PMC 85490. PMID 10733577.
  22. Dunant NM, Wisniewski D, Strife A, Clarkson B, Resh MD (May 2000). "The phosphatidylinositol polyphosphate 5-phosphatase SHIP1 associates with the dok1 phosphoprotein in bcr-Abl transformed cells". Cellular Signalling. 12 (5): 317–26. doi:10.1016/S0898-6568(00)00073-5. PMID 10822173.
  23. Baran CP, Tridandapani S, Helgason CD, Humphries RK, Krystal G, Marsh CB (October 2003). "The inositol 5'-phosphatase SHIP-1 and the Src kinase Lyn negatively regulate macrophage colony-stimulating factor-induced Akt activity". The Journal of Biological Chemistry. 278 (40): 38628–36. doi:10.1074/jbc.M305021200. PMID 12882960.
  24. Poe JC, Fujimoto M, Jansen PJ, Miller AS, Tedder TF (June 2000). "CD22 forms a quaternary complex with SHIP, Grb2, and Shc. A pathway for regulation of B lymphocyte antigen receptor-induced calcium flux". The Journal of Biological Chemistry. 275 (23): 17420–7. doi:10.1074/jbc.M001892200. PMID 10748054.
  25. Kavanaugh WM, Pot DA, Chin SM, Deuter-Reinhard M, Jefferson AB, Norris FA, Masiarz FR, Cousens LS, Majerus PW, Williams LT (April 1996). "Multiple forms of an inositol polyphosphate 5-phosphatase form signaling complexes with Shc and Grb2". Current Biology. 6 (4): 438–45. doi:10.1016/S0960-9822(02)00511-0. PMID 8723348.
  26. Arai A, Kanda E, Nosaka Y, Miyasaka N, Miura O (August 2001). "CrkL is recruited through its SH2 domain to the erythropoietin receptor and plays a role in Lyn-mediated receptor signaling". The Journal of Biological Chemistry. 276 (35): 33282–90. doi:10.1074/jbc.M102924200. PMID 11443118.
  27. Pumphrey NJ, Taylor V, Freeman S, Douglas MR, Bradfield PF, Young SP, Lord JM, Wakelam MJ, Bird IN, Salmon M, Buckley CD (April 1999). "Differential association of cytoplasmic signalling molecules SHP-1, SHP-2, SHIP and phospholipase C-gamma1 with PECAM-1/CD31". FEBS Letters. 450 (1–2): 77–83. doi:10.1016/S0014-5793(99)00446-9. PMID 10350061.
  28. van Dijk TB, van Den Akker E, Amelsvoort MP, Mano H, Löwenberg B, von Lindern M (November 2000). "Stem cell factor induces phosphatidylinositol 3'-kinase-dependent Lyn/Tec/Dok-1 complex formation in hematopoietic cells". Blood. 96 (10): 3406–13. doi:10.1182/blood.V96.10.3406. PMID 11071635.
  29. Wisniewski D, Strife A, Swendeman S, Erdjument-Bromage H, Geromanos S, Kavanaugh WM, Tempst P, Clarkson B (April 1999). "A novel SH2-containing phosphatidylinositol 3,4,5-trisphosphate 5-phosphatase (SHIP2) is constitutively tyrosine phosphorylated and associated with src homologous and collagen gene (SHC) in chronic myelogenous leukemia progenitor cells". Blood. 93 (8): 2707–20. doi:10.1182/blood.V93.8.2707. PMID 10194451.
  30. Leitges M, Gimborn K, Elis W, Kalesnikoff J, Hughes MR, Krystal G, Huber M (June 2002). "Protein kinase C-delta is a negative regulator of antigen-induced mast cell degranulation". Molecular and Cellular Biology. 22 (12): 3970–80. doi:10.1128/MCB.22.12.3970-3980.2002. PMC 133855. PMID 12024011.
  31. March ME, Lucas DM, Aman MJ, Ravichandran KS (September 2000). "p135 src homology 2 domain-containing inositol 5'-phosphatase (SHIPbeta ) isoform can substitute for p145 SHIP in fcgamma RIIB1-mediated inhibitory signaling in B cells". The Journal of Biological Chemistry. 275 (39): 29960–7. doi:10.1074/jbc.M003714200. PMID 10900203.
  32. AdisInsight. "AQX-1125". Springer. Archived from the original on 15 July 2016. Retrieved 20 July 2016.CS1 maint: BOT: original-url status unknown (link)
  33. World Health Organization, International Nonproprietary Names for Pharmaceutical Substances (INN): Proposed INN: List 115 (PDF)
  34. Ong CJ, Ming-Lum A, Nodwell M, Ghanipour A, Yang L, Williams DE, Kim J, Demirjian L, Qasimi P, Ruschmann J, Cao LP, Ma K, Chung SW, Duronio V, Andersen RJ, Krystal G, Mui AL (September 2007). "Small-molecule agonists of SHIP1 inhibit the phosphoinositide 3-kinase pathway in hematopoietic cells". Blood. 110 (6): 1942–9. doi:10.1182/blood-2007-03-079699. PMID 17502453.

Further reading
  • Overview of all the structural information available in the PDB for UniProt: Q92835 (Human Phosphatidylinositol 3,4,5-trisphosphate 5-phosphatase 1) at the PDBe-KB.
  • Overview of all the structural information available in the PDB for UniProt: Q9ES52 (Mouse Phosphatidylinositol 3,4,5-trisphosphate 5-phosphatase 1) at the PDBe-KB.
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